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Alzheimer's disease biomarker-guided diagnostic workflow using the added value of six combined cerebrospinal fluid candidates: Aβ1–42, total-tau, phosphorylated-tau, NFL, neurogranin, and YKL-40

  • Harald Hampel
    Affiliations
    AXA Research Fund & Sorbonne Université Chair, Paris, France

    Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Paris, France

    Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France

    Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France
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  • Nicola Toschi
    Affiliations
    Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy

    Department of Radiology, “Athinoula A. Martinos” Center for Biomedical Imaging, Boston, MA, USA

    Harvard Medical School, Boston, MA, USA
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  • Filippo Baldacci
    Affiliations
    AXA Research Fund & Sorbonne Université Chair, Paris, France

    Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Paris, France

    Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France

    Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France

    Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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  • Henrik Zetterberg
    Affiliations
    Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

    Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

    Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK

    UK Dementia Research Institute, London, UK
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  • Kaj Blennow
    Affiliations
    Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

    Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
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  • Ingo Kilimann
    Affiliations
    Department of Psychosomatic Medicine, University of Rostock & DZNE Rostock, Rostock, Germany
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  • Stefan J. Teipel
    Affiliations
    Department of Psychosomatic Medicine, University of Rostock & DZNE Rostock, Rostock, Germany
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  • Enrica Cavedo
    Affiliations
    AXA Research Fund & Sorbonne Université Chair, Paris, France

    Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Paris, France

    Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France

    Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France

    IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
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  • Antonio Melo dos Santos
    Affiliations
    Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Paris, France

    Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France

    Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France
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  • Stéphane Epelbaum
    Affiliations
    Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Paris, France

    Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France

    Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France
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  • Foudil Lamari
    Affiliations
    AP-HP, UF Biochimie des Maladies Neuro-métaboliques, Service de Biochimie Métabolique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Remy Genthon
    Affiliations
    Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Paris, France

    Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France

    Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France
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  • Bruno Dubois
    Affiliations
    Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Paris, France

    Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France

    Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France
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  • Roberto Floris
    Affiliations
    Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
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  • Francesco Garaci
    Affiliations
    Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy

    Casa di Cura “San Raffaele Cassino”, Cassino, Italy
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  • Simone Lista
    Affiliations
    AXA Research Fund & Sorbonne Université Chair, Paris, France

    Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Paris, France

    Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France

    Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France
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  • for theAlzheimer Precision Medicine Initiative (APMI)
Published:January 09, 2018DOI:https://doi.org/10.1016/j.jalz.2017.11.015

      Highlights

      • Interest in novel biomarkers of neurodegeneration is growing.
      • We measured novel and established cerebrospinal fluid biomarkers.
      • The diagnostic performances of all combinations were investigated.
      • We identified the biomarker combinations with the highest accuracy.
      • Longitudinal investigations are required to validate our data.

      Abstract

      Introduction

      The diagnostic and classificatory performances of all combinations of three core (amyloid β peptide [i.e., Aβ1–42], total tau [t-tau], and phosphorylated tau) and three novel (neurofilament light chain protein, neurogranin, and YKL-40) cerebrospinal fluid biomarkers of neurodegeneration were compared among individuals with mild cognitive impairment (n = 41), Alzheimer's disease dementia (ADD; n = 35), frontotemporal dementia (FTD; n = 9), and cognitively healthy controls (HC; n = 21), using 10-fold cross-validation.

      Methods

      The combinations ranking in the top 10 according to diagnostic accuracy in differentiating between distinct diagnostic categories were identified.

      Results

      The single biomarkers or biomarker combinations generating the best area under the receiver operating characteristics (AUROCs) were the following: the combination [amyloid β peptide + phosphorylated tau + neurofilament light chain] for distinguishing between ADD patients and HC (AUROC = 0.86), t-tau for distinguishing between ADD and FTD patients (AUROC = 0.82), and t-tau for distinguishing between FTD patients and HC (AUROC = 0.78).

      Conclusions

      Novel and established cerebrospinal fluid markers perform with at least fair accuracy in the discrimination between ADD and FTD. The classification of mild cognitive impairment individuals was poor.

      Keywords

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